Contrast agents are frequently used to obtain images differentiated between a diseased tissue such as a tumor and the surrounding tissue, in order to make clearer the contrast between the tissues containing similar components, thereby observing the position, size or state of the diseased tissue. As a method for differentiating between a diseased tissue and the surrounding tissue as described above, magnetic resonance imaging (MRI) technology shows superiority and stability. Various methods making it possible to observe the inside of the body have been developed to date, and MRI technology was developed most recently, but the applicability or utility of MRI shows a tendency to increase rapidly, because MRI is safer than other imaging technologies. Methods such as X-ray radiography, CT and PET comprise administering to the human body a radioactive substance which has not been proven to be harmless to the human body, and for this reason, these methods cannot be applied to patients who can have a genetic mutation, particularly cancer patients or pregnant women. However, MRI can appear as an imaging technology that overcomes such shortcomings, including radioactivity and limitations on subjects to be applied.
MRI images can be viewed by the use of contrast agents. As used herein, the term “MRI contrast agent” refers to an agent that shortens the relaxation times (such as T1 and T2) of human tissues to increase the contrast of images. Main examples of the MRI agent include agents comprising paramagnetic or super-paramagnetic materials. Contrast agents can be used either to amplify the signal of the whole or partial tissue of a target organ or to weaken the signal of the surrounding tissue, thereby maximizing the contrast between light and shade.
MRI contrast agents can be largely divided into gadolinium contrast agents that are used as T1 contrast agents, and iron oxide (ferroxide or ferric oxide) contrast agents that are used as T2 contrast agents.
Gadolinium that is used mainly as a T1 contrast agent has a very low molecular weight and a very strong toxicity, which cause many problems when it is used as a contrast agent. For this reason, a DTPA-Gd complex (Magnevist™, Bayer) consisting of diethylene triamine pentaacetic acid coordinated with gadolinium was developed and is a paramagnetic MRI contrast agent which was first approved by the FDA. However, DTPA-Gd still has the problems of gadolinium. Specifically, it has a half-life which is as extremely short as about 14 minutes, such that it is rapidly discharged with urine after administration (Hiroki Yoshikawa et al., Gazoshindan, 6, 959-969 (1986)). Thus, it is difficult to diagnose several areas in the body by injecting it once. Also, it is delivered non-specifically to a normal tissue and a diseased tissue, thus making it impossible to obtain images having a clear contrast. In addition, although it has reduced toxicity compared to the element gadolinium, the toxicity thereof is still problematic. Moreover, because it has a molecular weight that slightly exceeds about 500 Da, which cannot overcome previous problems such as nonspecific delivery or a short half-life, it is difficult to use as a contrast agent for diagnosing lesions in the liver. In MRI, contrast time varies depending on the magnetic field intensity of an MRI spectrometer to be used, and thus in the case of low-magnetic-field MRI spectrometers which are generally widely used, contrast time should be long. Therefore, the DTPA-Gd complex, which has a short half-life and lacks selectivity for diseased tissues, has limitations as MRI contrast agents.
Iron oxide-based MRI contrast agents are used as T2 contrast agents and have an advantage in that they can show significant contrast effects even when they are used in very small amounts. However, they have a significant problem in that it is difficult to determine the kind of disease, even though information about the position of disease is transferred due to their strong signals. Ferucarbotran (Resovist™, Schering), a typical iron oxide-based contrast agent, is a super-paramagnetic contrast agent that is used for MRI imaging of the liver according to the basic principle by which it accumulates in liver tissue through the reticuloendothelial system. However, it is unclear that ferucarbotran can indeed be delivered specifically to the liver through the reticuloendothelial system so that it is effective in obtaining an accurate image for liver disease.